Current Computer-Aided Drug Design

Subhash C. Basak
Departments of Chemistry, Biochemistry & Molecular Biology University of Minnesota Duluth
Duluth, MN 55811


Computer-Aided Drug Design for Typical and Atypical Antipsychotic Drugs: A Review of Application of QSAR and Combinatorial Chemistry Methods - Tools for New Antipsychotics Design

Author(s): S. Avram, A.- L. Milac, M. L. Flonta.


The central nervous system (CNS) is endowed with very efficient protection mechanisms. However, the same mechanisms that protect it, sometimes can be an enemy for therapeutic applications. In this way, many antipsychotic drugs used, are ineffective in the treatment of cerebral diseases such as schizophrenia. Many typical and atypical neuroleptics are very efficient against the positive symptoms, but not against the negative symptoms. To reduce the inefficiency of known neuroleptics, many research efforts have recently focused on the development of new strategies for new neuroleptics drug design. For this reason it was necessary to apply very fast and precise techniques, such as: QSAR (Quantitative Structure-Activity Relationships) and combinatorial chemistry methods, capable to analyze and predict the biological activity for these structures, taking in account the possible changes of the molecular structures. This review intends to detail recent advances in the field of structure-activity relationship and combinatorial chemistry applied to neuroleptics. The antipsychotic activities (log ED50) of potent neuroleptics as indole derivatives, were correlated with pharmacokinetic parameters namely: molecular volume (V), globularity (G), Octanol/water partition coefficient (logP), solubility(S), dipole moment, polarizability. QSAR studies of benzothiazepine derivatives as potent neuroleptics are presented. In addition, the 3D-QSAR methods such as Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were applied for a set of dopamine D4 receptor antagonists. The combinatorial chemistry was used to develop a large chemical library starting from 5-hydroxytryptamine2A receptor antagonists used as antipsychotics.

Keywords: schizophrenia, typical and atypical neuroleptics, d-qsar, combinatorial chemistry

Order Reprints Order Eprints Rights & PermissionsPrintExport

Article Details

Year: 2005
Page: [347 - 364]
Pages: 18
DOI: 10.2174/157340905774330273
Price: $58